An effective vaccine against hepatitis B virus (HBV) infection has been available for more than two decades, but 400 million people—more than 5% of the world's population—are chronically infected with HBV. More than 1 million people die each year from HBV-related liver cirrhosis and hepatocellular carcinoma. (Ganem, D., Prince, A. M. (2004) Hepatitis B virus infection—natural history and clinical consequences, N Engl J Med 350:1118-29.)
HBV is mainly not directly cytopathic. The immune response to viral antigens is thought to be responsible for both liver disease and viral clearance following HBV infection. (Ganem et al., 2004.) Immune responses with virus-specific CD8+ cytotoxic T lymphocytes (CTLs) and CD4+ T-helper (Th) cells play key effector and regulatory roles in both liver pathogenesis and viral clearance. HBV acute infection in immunocompetent adults usually results in a transient self-limited liver disease followed by viral clearance, and is characterized by vigorous polyclonal CTLs and type 1-Th responses specific for a number of epitopes within HBV viral proteins.
Patients with acute viral infection, who successfully clear the virus, display a multispecific polyclonal cytotoxic T-lymphocyte (CTL) response specific for a number of epitopes within the core, polymerase, and envelope proteins. Viral specific, e.g., HBV-specific Th cells are also activated. Multispecific Th1-like responses have been detected in patients successfully clearing HBV after acute infection. (Chisari et al. (1995) Hepatitis B virus immunopathogenesis, Annu Rev Immunol 13:29-60.)
The HBV-specific T-cell response is weak or undetectable in patients who develop chronic infection and the mechanisms responsible for T cell hypo-responsiveness or tolerance in chronic infection are not completely understood. In chronically infected patients, the peripheral CD8+ T cell response is undetectable or weak and the CD4+ T cell response is much less vigorous than in patients who clear the infection.
Although functional effector T cells are initially generated during the early stages of infection, they gradually lose function during the course of a chronic infection by upregulating the programmed death 1 (PD-1) inhibitory receptor. (Chisari, et al., 1995.) Accordingly, in chronic patients who spontaneously clear hepatitis B surface antigen (HBsAg) and develop neutralizing anti-HBs antibodies, HBV-specific T-cell responses have been detected in the blood just before seroconversion. It has also been shown that effective therapeutic reduction of HBV viral load resulted in a transient restoration of HBV-specific CD4+ and CD8+ T-cell responses in the blood from patients with chronic hepatitis B.
The mechanisms responsible for T cell hypo-responsiveness and exhaustion during HBV persistent infection are still not completely understood. (Rehermann, B., Nascimbeni M. (2005) Immunology of hepatitis B virus and hepatitis C virus infection, Nat Rev Immunol 5:215-29.) Exhausted T cell responses observed during persistent viral infection reflect a balance between effector functions required to eliminate the pathogen and the potential of T cells to cause immunopathology. Impaired dendritic cell functions and the presence of CD4+CD25+ regulatory T cells also contribute to the viral persistence. Moreover, the liver particularly biases the intrahepatic T cell response towards tolerance or anergy.
Active immunotherapy based on specific viral-epitopes and hepatitis vaccine injection provide promising approaches in inducing efficient cellular immune responses. A previous study of a phase I clinical trial suggested that HBV DNA vaccination could specifically restore T-cell responsiveness in chronic HBV carriers. However, the activation of HBV-specific T-cells appeared to be transient and was followed by a progressive decline along the DNA injections. (Mancini-Bourgine, M., Fontaine, H., Scott-Algara, D., Pol, S., Brechot, C., Michel, M. L. (2004) Induction or expansion of T-cell responses by a hepatitis B DNA vaccine administered to chronic HBV carriers, Hepatology 40:874-82.) Bypassing the potential tolerance of T cells to HBV antigens, therefore, turns out to be a most crucial point in immunotherapy.
Collectively this suggests that, to treat chronic hepatitis, e.g., HBV, infection, the intrahepatic T cell responses should be switched from a state of exhaustion or anergy to a state in which the effector T cells are fully efficient. (Bertoletti, A., Gehring, A. J. (2006) The immune response during hepatitis B virus infection, J Gen Virol 87:1439-49; Rehermann et al., 2005.)
Accordingly, there exists a need in the art for new therapies for the treatment of chronic hepatitis infection, for example, hepatitis B infection. These therapies should also be generally useful in the treatment of other viral persistent infections. The therapies should also be specific for the cells infected with the virus involved in the persistent infection. For example, in the case of a hepatitis viral infection, the therapies should be specific for hepatitis virus infected cells, especially human hepatocytes. (Rehermann, et al., 2005.)